Serum phosphorus levels are associated with endothelial dysfunction in hypertensive patients.

BACKGROUND AND AIMS: Recent data demonstrated that serum phosphorus, within the normal range, is an independent predictor of atherosclerotic cardiovascular disease, independently of renal function. Traditional cardiovascular risk factors are important mediators of endothelial dysfunction, the early step of atherosclerosis. We designed this study to evaluate a possible correlation between serum phosphorus and endothelium-dependent vasodilation, evaluated by the strain-gauge plethysmography, in naïve hypertensives. METHODS AND RESULTS: We investigated by strain-gauge plethysmography, the relationship between forearm blood flow (FBF) response to acetylcholine (ACh) and serum phosphorus in 500 patients with uncomplicated, never-treated, essential hypertension, divided by phosphorus tertiles. There were no significant differences among tertiles with the exclusion of forearm blood flow (FBF). Phosphorus (ß = -0.454; P = 0.0001), estimated-glomerular filtration rate (e-GFR, by CKD-EPI formula) (ß = 0.261; P = 0.0001), gender (ß = 0.215; P = 0.0001), BMI (ß = -0.086; P = 0.018), HDL-cholesterol (ß = 0.077; P = 0.036) were significantly related to endothelium-dependent vasodilation. In an additional analysis including serum high sensitivity C-reactive protein (hs-CRP) (measured in 400 patients) in the same model, the link between serum phosphorus and ACh-stimulated FBF did not change (ß = -0.422; P = 0.0001). Clinically relevant, 0.1 mg of phosphorus increase is associated with a reduction of 22% of ACh-stimulated FBF. On multiple logistic regression analysis, the risk of endothelial dysfunction was about twice higher in patients in the second (OR = 1.754, 95% CI = 1.055-2.915; P = 0.030) and three-fold higher in the third tertile (OR = 2.939, 95% CI = 1.598-5.408; P = 0.0001) in comparison with those in the first tertile of phosphorus. CONCLUSION: An impaired ACh-stimulated FBF is associated with serum phosphorus levels, within the normal range, in hypertensives.

Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide-treated human renal proximal tubular cells by alpha-erythropoietin.

OBJECTIVE: Erythropoietin has been shown to have a protective effect in certain models of ischaemia-reperfusion, and in some cases the protection has been correlated with activation of signalling pathways known to play a role in cell survival and proliferation. We have studied whether erythropoietin would overcome direct toxic effects of hydrogen peroxide (H(2)O(2)) treatment to human renal proximal tubular (HK-2) cells. MATERIALS AND METHODS: HK-2 cells were incubated with H(2)O(2) (2 mm) for 2 h with or without erythropoietin at concentrations of 100 and 400 U/ml, and cell viability/proliferation was assessed by chemical reduction of MTT. Changes in phosphorylation state of the kinases Akt, glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) were also analysed. RESULTS: Cells incubated with H(2)O(2) alone showed a significant decrease in viability, which did not significantly change by addition of erythropoietin at concentration of 100 U/ml, but was further reduced when concentration of erythropoietin was increased to 400 U/ml. Phosphorylation state of the kinases Akt, GSK-3beta, mTOR and ERK1/ERK2 of H(2)O(2)-treated HK-2 cells was slightly altered in the presence of erythropoietin at concentration of 100 U/ml, but was significantly less in the presence of erythropoietin at a concentration of 400 U/ml. Phosphorylation of forkhead transcription factor FKHRL1 was diminished in cells incubated with H(2)O(2) and erythropoietin at a concentration of 400 U/ml. CONCLUSIONS: Erythropoietin, at high concentrations, may significantly increase cellular damage in HK-2 cells subjected to oxidative stress, which may be due in part to decrease in activation of important signalling pathways involved in cell survival and/or cell proliferation.

Monitoring chronic hemodialysis patients: a questionnaire-based survey.

BACKGROUND: The monitoring program for patients on regular hemodialysis treatment (RDT) is not well defined yet by current international guidelines (CIG). METHODS: To evaluate the extent to which CIG are implemented, we sent a questionnaire to 100 Italian hemodialysis units (DU) with questions concerning: (a) the frequency with which routine tests were performed for the follow-up of patients on RDT; (b) which other non-routine tests were performed. We analyzed the response data and compared them with the CIG. RESULTS: We received 37 replies. We found several differences between the monitoring program of our respondents and the CIG. CONCLUSION: Because of the small number of responses, this survey is only preliminary; however, it shows the difficulty nephrologists have in using the CIG to create a correct monitoring program in patients on RDT. Although our analysis is limited to 37 DUs, it suggests that specific guidelines are necessary to optimize the management of patients on RDT.

Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings.

In mucopolysaccharidoses, upper airway obstruction has multiple causative factors and progressive respiratory disease may severely affect morbidity and mortality. In a cross-sectional study over 2 years we evaluated upper airway obstructive disease through overnight polysomnography, upper airway computed tomography and nasal endoscopy in 5 children and 6 adults with mucopolysaccharidoses of various types. Measurements of apnoea and apnoea-hypopnoea index, arousal index, and sleep efficiency were obtained through polysomnography. Retropalatal and retroglossal spaces were calculated through computed tomography, and the degree of adenoid hypertrophy was assessed through endoscopy. Apnoea index and apnoea-hypopnoea index were significantly higher in children than in adults with mucopolysaccharidoses (p = 0.03 and p = 0.03, respectively). Compared to healthy controls, retropalatal and retroglossal spaces were significantly smaller in children (p = 0.03 and p = 0.004, respectively) or adults with mucopolysaccharidoses (p = 0.004 and p = 0.004, respectively). All subjects had adenoid hypertrophy causing first-degree (36%) or second-degree (64%) obstruction at endoscopy. Overnight polysomnography, upper airway computed tomography and nasal endoscopy are useful tools for diagnosing obstructive sleep apnoea syndrome in mucopolysaccharidoses, and identifying the site and severity of airway obstruction.

[Fabry nephropathy in a female with superposed IgA glomerulonephritis]. / Nefropatia da malattia di Fabry in donna eterozigote con sovraimposta glomerulonefrite da IgA.

BACKGROUND: In Anderson-Fabry disease (AFd), the kidney is affected in all hemizygous males and in some heterozygous females. Female carriers can present subtle renal abnormalities due to glycosphingolipid (GSL) accumulation within renal cells. Renal biopsy is rarely performed in female Fabry patients because clinical renal manifestations are usually lacking. However, female carriers can accumulate GSL in their renal cells despite the absence of clinically evident kidney disease. CASE REPORT: We performed a kidney biopsy in a 52-year-old female patient, a Fabry disease carrier. The patient showed normal glomerular filtration rate, persistent microhematuria and proteinuria (about 1.7 g/24 hr), cornea "verticillata", and evident left ventricular hypertrophy. The molecular study documented a missense mutation R227Q in exon 5 of the alpha-galactosidase A gene. Optical microscopy showed electron-dense mesangial deposits due IgA glomerulonephritis, as confirmed by immunofluorescence. We decided to start therapy with angiotensin-converting enzyme inhibitors (ACE-I). After 8 months of treatment, the patient demonstrated proteinuria of 0.9 g/24 hr. To decide when to start treatment using enzyme replacement therapy (ERT) with human recombinant GAL A (Fabrazyme), we decided to perform an electron microscopy study of the renal biopsy. The renal ultrastructural findings were typical GSL inclusions in all kinds of glomerular cells, in tubular epithelial cells and in endothelial cells of interstitial capillaries, confirming the hypothesis of Fabry nephropathy. Consequently, Fabrazyme was given at a standard dose of 1 mg/kg every 2 weeks. After 24 months of combined treatment (ACE-I-Fabrazyme), proteinuria decreased to 0.2 g/24 hr. CONCLUSIONS: The importance of performing the ultrastructural examination of the kidney biopsy is stressed, especially in heterozygous Fabry patients to evaluate the need to treat them with ERT and to evaluate the degree of renal involvement.

Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry's disease.

Fabry's disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase that results in an accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system. Fabry cardiomyopathy, characterized by progressive severe concentric left ventricular (LV) hypertrophy, is very frequent and is the most important cause of death in affected patients. Enzyme replacement therapy (ERT) allows a specific treatment for this disease, however, there are very few data on the effectiveness of therapy on cardiac involvement. Nine patients with Fabry cardiac disease were studied on basal condition and after 6 and 12 months of treatment with algasidase beta (Fabrazyme). A complete clinical, electrocardiographic and echocardiographic evaluation was performed in all patients. Interpretable Doppler recordings of transmitral flow and pulmonary flow velocity curves were also acquired. At baseline, the patients with Fabry's disease had increased LV septum and posterior wall thickness, normal LV fractional shortening, LV ejection fraction, normal Doppler parameters of mitral inflow but a duration of pulmonary vein flow velocity wave exceeding that of the mitral wave at atrial systole. ERT did not affect heart rate and arterial pressure. LV internal diameters did not change, there was a slight but not significant decrease in the LV posterior wall thickening and a progressive decrease in the interventricular septum thickening (p < 0.025) and in LV mass (p < 0.001) The difference in duration between pulmonary vein flow velocity wave and mitral wave at atrial systole significantly decreased (p < 0.001). These results suggest that ERT in patients with Fabry cardiomyopathy is able to reduce the LV mass and ameliorate the LV stiffness.

[Anderson-Fabry's disease: diagnostic problems, therapeutic relevance, and clinical experience in the treatment of the disease with enzyme replacement therapy in nephropathic patients]. / Malattia di Anderson-Fabry: problematiche diagnostiche, attualità terapeutiche ed esperienza clinica nel trattamento della malattia con terapia enzimatica sostitutiva in pazienti nefropatici.

Aim of this study was to confirm the initial results of a clinical trial on the treatment of Fabry's disease carried out in 13 Italian Nephrology Units. Fabry's disease is a rare, X-linked inherited disease, characterized by a-galactosidase (a-GAL) deficiency, a lysosomial enzymatic activity that results in the accumulation of neutral glycosphingolipids in the endothelial cells of the whole body, and causes painful crises, acroparesthesiae, angiokeratomas, corneal and lens dystrophy, and progressive damage to kidneys, heart and central nervous system, as well as potentially leading to death. The present availability of the recombinant form of a-GAL allows us to prevent or stop the long-term complications of this disease. A clinical trial, generously supported by Genzyme, was started on February 2001. In this trial 20 patients affected by Fabry's disease were periodically treated with agalsidase-beta, the commercial form of the enzyme. The initial results of the trial have indicated that the drug is capable of reducing both the number and intensity of painful crises, improving the patient's sensation of well-being, thus suggesting that this therapeutic approach might theoretically increase life expectancy in these patients.

Polycystin-1 interacts with intermediate filaments.

Polycystin-1, the protein defective in a majority of patients with autosomal dominant polycystic kidney disease, is a ubiquitously expressed multi-span transmembrane protein of unknown function. Subcellular localization studies found this protein to be a component of various cell junctional complexes and to be associated with the cytoskeleton, but the specificity and nature of such associations are not known. To identify proteins that interact with the polycystin-1 C-tail (P1CT), this segment was used as bait in a yeast two-hybrid screening of a kidney epithelial cell library. The intermediate filament (IF) protein vimentin was identified as a strong polycystin-1-interacting partner. Cytokeratins K8 and K18 and desmin were also found to interact with P1CT. These interactions were mediated by coiled-coil motifs in polycystin-1 and IF proteins. Vimentin, cytokeratins K8 and K18, and desmin also bound directly to P1CT in GST pull-down and in in vitro filament assembly assays. Two observations confirmed these interactions in vivo: (i) a cell membrane-anchored form of recombinant P1CT decorated the IF network and was found to associate with the cytoskeleton in detergent-solubilized cells and (ii) endogenous polycystin-1 distributed with IF at desmosomal junctions. Polycystin-1 may utilize this association for structural, storage, or signaling functions.

Case of Myhre syndrome with autism and peculiar skin histological findings.

Myhre syndrome (MS) (MIM 139210) is a rare disorder characterized by short stature, mental retardation, muscular build, blepharophimosis, and decreased joint mobility. We report on a 14-year-old boy with clinical findings consistent with a diagnosis of Myhre syndrome, associated with autism and peculiar skin histological findings.

Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs.

Edema and acute renal failure.

Acute renal failure (ARF) with overhydration and edematous state may follow Acute endocapillary proliferative glomerulonephritis and extracapillary glomerulonephritis, because of reduction of the glomerular capillary area available for filtration. But ARF may also be observed in edematous patients with minimal change nephrotic syndrome; it may require dialysis until recovery and is attributable to some of the following factors: (1) ischemic renal injury, (2) hypovolemia, (3) interstitial edema with tubular collapse, (4) redistribution of renal blood flow (RBF) from cortical to juxtaglomerular nephrons, (5) decrease of capillary filtration coefficient (Kf), (6) use of nonsteroidal antiinflammatory drugs. Congestive heart failure also leads to prerenal azotemia and edema formation secondary to salt retention. Multiple organ dysfunction syndrome (MODS) is frequently associated with ARF; but edema occurs even without ARF in septic patients with severe inflammatory response syndrome (SIRS). ARF may follow severe burns; burned patients are frequently edematous because of a rapid leak of fluid from the vascular bed into the wound; edema in undamaged areas occurs in the 'flow phase', because of a fall of oncotic pressure because of massive loss of plasma proteins into the wound. Edema must be treated with diuretics or by dialysis.

Sodium retention in preascitic stage of cirrhosis.

Renal Na+ handling abnormalities have been shown in preascitic cirrhosis. To investigate the underlying pathophysiology, the effects of different sodium intakes on Na(+) balance and renal hemodynamics were assessed at 100 mEq Na+/day (low-sodium diet [LSD]) and after 6 days of 250 mEq Na+/day (high-sodium diet [HSD]). Eight asymptomatic patients with cirrhosis (Pugh-Child A class) (PAC) and 10 healthy controls (CON) were studied. At HSD, although CON readjusted Na+ excretion within the fourth day, PAC did not reach the new balance and developed a final greater Na+ retention (+437 mEq in PAC v +228 mEq in CON, P<.001). In PAC, fractional Na+ excretion (FENa) was significantly lower than in CON at LSD (P<.05), and, after HSD, increased in both groups (P<.05). In PAC, renal vascular resistances (RVR) at LSD resulted lower than in CON (P<.05) and failed to decrease after HSD. As a consequence, after HSD, glomerular filtration rate and renal plasma flow failed to increase in PAC. PRA and plasma aldosterone were significantly lower in PAC, than in CON at LSD (P<.05), and decreased in both groups after HSD (P<.05). Proximal Na+ reabsorption (RProx) [as indicated by fractional free water clearance measured in a state of maximal water diuresis] at LSD was lower in PAC than in CON (P<.05) and decreased in both groups after HSD (P<.05). In summary, early stages of cirrhosis are characterized by: (1) a reduction of RVR, probably associated with splanchnic vasodilation; (2) a Na+ retention already at LSD, as indicated by the lower FENa observed in PAC, that produces extracellular volume (ECV) expansion, with a consequent RProx and renin-angiotensin-aldosterone axis (RAS) suppression; (3) a greater Na+ retention after HSD, associated with an abnormal adaptation of renal hemodynamic, a greater ECV expansion and a consequent Rprox and RAS suppression. These data show the presence of early renal hemodynamic dysfunction in PAC. Our findings also show in this phase of the disease a preserved adaptation of RProx and RAS, thus suggesting that the observed tubular Na+ reabsorption derangement is probably related to abnormal ANP behavior.

Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects.

BACKGROUND: It is still unclear whether age per se is associated with preservation of renal functional reserve, that is, of the increase in glomerular filtration rate (GFR) induced by appropriate vasodilating stimulus. METHODS: To gain insights into this issue, we evaluated the renal response to a maximal vasodilating stimulus, represented by the combined infusion of mixed amino acid solution (AA) and dopamine at renal dose (D), in 10 young subjects (median age of 30 years, range of 19 to 32) and in 11 subjects of older age (median age of 67 years, range of 65 to 76). Two further age-matched groups of young (N = 15) and older (N = 11) living kidney donors underwent renal needle biopsy immediately before nephrectomy to perform semiquantitative scoring (0 to 3) of arteriosclerosis in intrarenal arteries. All of the study subjects were nonsmokers with healthy status proven by extensive diagnostic evaluation excluding any risk factor of renal dysfunction. RESULTS: Basal renal plasma flow (RPF) and GFR were proportionally lower in older subjects (RPF, 361 +/- 29 vs. 618 +/- 34 mL/min/1.73 m(2), P < 0.001; GFR, 79 +/- 4 vs. 127 +/- 5.8 mL/min/1.73 m(2), P < 0.001). After AA + D, a significant increase of RPF and GFR was observed in both groups, but the older subjects exhibited a smaller percentage increment (RPF, 25.5 +/- 4.8 vs. 42.4 +/- 5.8, P < 0.05; GFR, 19.6 +/- 5.7 vs. + 33.8 +/- 6.4, P < 0.05). Furthermore, the maximal vasodilating stimulus was not able to restore renal hemodynamics in older subjects to the level measured in young controls at baseline. Renal vascular resistances were higher (P < 0.05) in the older subjects both at baseline (0.19 +/- 0.02 vs. 0.09 +/- 0.004 mm Hg/mL/min) and after AA + D (0.14 +/- 0.01 vs. 0.06 +/- 0.004). Light microscopy examination detected the presence of a greater degree of arteriosclerosis at the level of interlobular and arcuate arteries (0.89 +/- 0.15 vs. 0.45 +/- 0.08) and interstitial fibrosis/tubular atrophy (1.18 +/- 0.13 vs. 0.53 +/- 0.13) in older than in young subjects. CONCLUSIONS: Therefore, aging has adverse effects on renal function despite the absence of any risk factor for renal disease, including chronic smoking: (1) GFR and RPF are lower, and (2) the renal response to maximal vasodilating stimulus is impaired. These aging-related alterations of renal hemodynamics are possibly due to organic lesions in renal vasculature.

Serine-threonine protein kinase Akt does not mediate ischemic tolerance after global ischemia in the gerbil.

The protein kinase Akt/PKB has been implicated in antiapoptosis and neuronal survival. The authors now show that Akt is phosphorylated in the hippocampus during the early reperfusion period after 3.5 minutes bilateral carotid artery occlusion (BCAO) in the gerbil. Repeated sublethal ischemia induces ischemic tolerance, which is known as ischemic preconditioning. Ischemic preconditioning does not affect the amount of Akt protein, but rather decreases the phosphorylation of Akt at Ser-473 after 10 minutes reperfusion after 3.5 minutes BCAO. These results suggest that although Akt may play a role in neuronal survival after ischemia, it may not play a role in ischemic tolerance by preconditioning.

Effect of posture on sodium excretion and diuretic efficacy in nephrotic patients.

It is well known that posture affects natriuresis in cirrhosis and heart failure. This study evaluates the role of posture on spontaneous urinary salt excretion (U(Na)V) and diuretic-induced natriuresis in nephrotic patients with mild renal impairment. U(Na)V and plasma concentrations of the main hormones involved in sodium regulation were evaluated at baseline (Baseline) and after furosemide administration (20 mg intravenously at 8:00 AM [Diuretic]) in seven nephrotic patients with mild renal impairment (creatinine clearance, 68.5 +/- 7.6 mL/min) in either the supine or upright position for 6 hours (from 8:00 AM to 2:00 PM). At baseline, U(Na)V was greater in the supine than upright position (sodium, 51.8 +/- 6.2 versus 38.3 +/- 6.1 mEq/d; P: < 0.01). Similarly, furosemide was more effective in increasing U(Na)V in the supine (sodium, 51.8 +/- 6.2 to 87.4 +/- 9.1 mEq/d; P: < 0.005) than upright position (sodium, 38.3 +/- 6.1 to 59.0 +/- 6.8 mEq/d; P: = not significant). Consequently, body weight decreased in the supine but not the upright position (-0.73 +/- 0.15 versus -0.17 +/- 0.22 kg; P: < 0. 05). Peripheral renin activity (PRA) and plasma aldosterone (Aldo) concentrations were greater in the upright than supine position at both Baseline and Diuretic. A similar pattern was observed for hematocrit, used as an index of plasma volume. In addition, a positive correlation was detected between hematocrit and PRA (r = 0.89; P: < 0.001) in the upright position. Postural changes did not influence plasma concentrations of atrial natriuretic peptide. These data indicate that in nephrotic patients with mild impairment of glomerular filtration rate, the upright position causes a reduction in plasma volume; this hypovolemia activates the renin-Aldo system responsible for sodium retention in unstimulated conditions and a blunted natriuretic response to furosemide.

Role of different dialysis membranes in the release of interleukin-6-soluble receptor in uremic patients.

BACKGROUND: Interleukin-6 (IL-6) exerts its actions through a cell-surface receptor system that consists of two transmembrane subunits: the IL-6 binding glycoprotein gp 80 (IL-6R) and the signal-transducing component (gp 130). Soluble forms of the IL-6R (sIL-6R) are generated by shedding of the membrane-associated proteins. The sIL-6R binds the ligand IL-6 with comparable affinity as the membrane-associated IL-6R and enhances the actions of IL-6. METHODS: Our aim was to evaluate the role of both uremia and different dialysis membranes on peripheral blood mononuclear cell (PBMC) release (either in absence or in presence of mitogen stimulation) and plasma levels of sIL-6R. Ten patients chronically dialyzed with cuprophan membranes (CU), eight patients on regular dialysis treatment with polymethylmethacrylate (PMMA) membranes, 11 uremic nondialyzed patients (UR), and 12 healthy subjects (CON) were included in the study. RESULTS: PBMCs harvested from CU spontaneously released significantly (P < 0.01) greater amounts of sIL-6R (881.8 +/- 80.1 pg/mL), as compared with CON (267.5 +/- 26.5 pg/mL), UR (258.4 +/- 38.1 pg/mL), and PMMA (288.4 +/- 24.6 pg/mL). Under mitogenic stimulation, the sIL-6R release was significantly (P < 0.01) increased in all groups. The greater PBMC production of sIL-6R in CU was followed by significantly (P < 0.01) higher levels of circulating soluble receptors (48.7 +/- 2.5 ng/mL, 60%), as compared with CON (30.5 +/- 1.9 ng/mL). UR also showed high circulating levels of sIL-6R (53.3 +/- 5.9 ng/mL), probably secondary to an impaired urinary excretion. Circulating levels of sIL-6R in PMMA were comparable to CON (30.3 +/- 3.3 ng/mL). Either the absence of monocyte activation or the adsorption of sIL-6R on the hydrophobic PMMA surface could explain this finding. CONCLUSIONS: These results suggest an important role for poor dialysis biocompatibility of CU on the release of sIL-6R, which increases sIL-6R plasma levels, thereby enhancing the inflammatory effects of IL-6.

Current indications for renal biopsy: a questionnaire-based survey.

Indications for renal biopsy are still ill defined. We recently sent a detailed questionnaire to 360 nephrologists in different areas of the world with the aim of providing information on this critical issue by evaluating the replies. The questionnaire was organized in four sections that included questions on renal biopsy indications in patients with normal renal function, renal insufficiency, and a transplanted kidney. In addition, the questions included methods applied to each renal biopsy procedure and to specimen processing. We received 166 replies; North Europe (50 replies), South Europe (47 replies), North America (31 replies), Australia and New Zealand (24 replies), and other countries (14 replies). In patients with normal renal function, primary indications for renal biopsy were microhematuria associated with proteinuria, particularly greater than 1 g/d of protein. In chronic renal insufficiency, kidney dimension was the major parameter considered before renal biopsy, whereas the presence of diabetes or serological abnormalities was not considered critical. In the course of acute renal failure (ARF) of unknown origin, 20% of the respondents would perform renal biopsy in the early stages, 26% after 1 week of nonrecovery, and 40% after 4 weeks. In a transplanted kidney, the majority of nephrologists would perform a renal biopsy in the case of graft failure after surgery, ARF after initial good function, slow progressive deterioration of renal function, and onset of nephrotic proteinuria. The last section provided comprehensive information on the technical aspects of renal biopsy. This survey represents the first attempt to provide a reliable consensus that can be used in developing guidelines on the use of kidney biopsy.

Hemodialysis-related lymphomononuclear release of interleukin-12 in patients with end-stage renal disease.

Interleukin-12 (IL-12) is a cytokine produced by peripheral blood mononuclear cells (PBMC) that causes interferon-gamma (IFN-gamma) production and enhancement of cell-mediated cytotoxicity. To clarify the role of hemodialysis biocompatibility on IL-12 production and uremic immunodeficiency, we have studied the IL-12 and IFN-gamma release by PBMC harvested from 12 patients dialyzed with cuprophan membrane (CU), eight patients dialyzed with polymethylmethacrylate membrane (PMMA), and eight nondialyzed uremic patients (UR). Ten healthy subjects constituted the control group (CON). PBMC were cultured for 48 h with and without nonspecific mitogen stimulation. In unstimulated conditions, CU showed an IL-12 PBMC production higher than CON, UR, and PMMA (46.67 +/- 30.13 versus 2.56 +/- 1.38, 6.16 +/- 7.09, and 4.62 +/- 4.76 pg/ml, respectively; P < 0.01). IL-12 production was correlated with C3a concentration measured at the outlet of hemodialyzer after 15 min of dialysis (r = 0.69, P < 0.01). IL-12 release in CU remained unchanged under mitogen stimulation (44.34 +/- 23.86 pg/ml) and was lower than in CON, UR, and PMMA (66.0 +/- 12.41, 68.37 +/- 25.78, and 67.75 +/- 22.61 pg/ml, respectively; P < 0.05). IFN-gamma production was similar, in unstimulated conditions, in all groups. Under stimulation, IFN-gamma release was lower in CU (13.42 +/- 12.04 IU/ml) than in CON, UR, and PMMA (51.84 +/- 30.74, 32.16 +/- 13.86, and 32.16 +/- 13.86 IU/ml, respectively; P < 0.01). These results demonstrate that hemodialysis with CU induces monocyte activation with an enhanced release of IL-12. On the contrary, stimulated PBMC production of both IL-12 and IFN-gamma is lower in these patients than in CON, UR, and PMMA. The altered release of these cytokines could play a role in cell-mediated immunodeficiency of the uremic patients dialyzed with CU.